Project Summary Alzheimer?s disease (AD) is a progressive neurodegenerative disease characterized by progressive memory loss, cognitive decline, synaptic loss, and abnormal behavior. Recent emerging data from our lab suggests that mitochondrial dysfunction may effect on mitophagy and may play a pivotal role in AD pathogenesis and progression. However, the relationship between Drp1 mitophagy remains obscure. In this proposal, we propose to elucidate the role of reduced Drp1 in preventing the progression of AD by promoting mito- and autophagy Preliminary findings from the Reddy lab suggest that there is an increase in mitochondrial fragmentation, and a reduction in mitochondrial biogenesis and in synaptic function, in 6- and 12-month-old tau mice. These changes were reversed in the presence of reduced Drp1 in 6- an 12-month-old tau mice, suggesting that a reduction of Drp1 may decrease the production of phosphorylated tau, reduce mitochondrial dysfunction, maintain mitochondrial dynamics, and enhance mitochondrial biogenesis and synaptic activity. We also found a failure in mitophagy in 12-month-old APP mice. The mechanisms underlying reduced Drp1 remain to be elucidated in the proposed research, the effect of Drp1 on mitophagy mechanisms of tau mice will be determined. In Aim 1 of this project, we will identify the expressions of mitophagy genes and proteins, such as PINK1 and PINK1 receptors NDP52, Optineurin to determine the role of Drp1. We will also study p62, also called sequestosome1 (SQSTM1), the selective cargo receptor for mitophagy. In Aim 2, using AAV gene transfer, we will decipher the mito- and autophagy mechanisms!with the over expression of Drp1expression in tau mice. In a preliminary study, PINK1 was found to activate mitophagy without parkin by recruiting autophagy receptors, such as Optineurin and NDP52. This novel mechanism in tau mice clearly reveals the protective role of reduced Drp1 in promoting mitophagy mechanisms for clearing accumulated phosphorylated Tau protein !